DESCRIPTION: (Applicant's Abstract) The general aim of this proposal is to study with brain imaging the neurochemical mechanisms underlying sensitization to psychostimulants in humans. Cocaine produces its reinforcing effects by blockade of the dopamine (DA) transporter, leading to an increase in DA synaptic concentration. In rodents, repeated exposure to psychostimulants such as amphetamine or cocaine results in a enhanced behavioral response to subsequent exposures, a phenomenon referred to as sensitization. Behavioral sensitization to psychostimulants has also been described in humans and is believed to play a role in addiction. Enhanced stimulant-induced DA release is the neurobiological mechanism underlying behavioral sensitization to stimulants in rodents. Until recently, the relevance of this observation to humans could not be assessed. We recently developed a noninvasive method using SPECT and the radiotracer [l23I]IBZM to measure amphetamine-induced DA release in humans. In specific aim #1, we propose to measure amphetamine-induced DA release with SPECT and [l23I]IBZM in 24 cocaine abusers after 3 weeks of abstinence and 24 healthy control subjects, never previously exposed to psychostimulants, matched for age, gender, race and socioeconomic status. The hypothesis is that enhanced DA release will be observed in abstinent cocaine abusers. The DA transporter gene (DAT1 ) presents a variable number of tandem repeat (VNTR) in the 3' untranslated region of the gene. In humans, allele frequency for 9 and 10 repeats are about 30% and 70%, respectively. Cocaine-induced paranoia, a well characterized manifestation of sensitization in humans, is associated with the 9 repeat allele at this locus. We previously showed with SPECT and [l23I]IBZM that psychostimulant-induced psychotic reaction was associated with increased DA release. In addition, preliminary data suggest that amphetamine-induced DA release is increased in carriers of the 9 allele. Thus, the presence of the 9 allele might represent a risk factor for sensitization to psychostimulants. In specific aim 2, we propose to compare amphetamine-induced DA release in 18 "9-9" and 18 "10-10" homozygote subjects, never previously exposed to psychostimulants, to test the hypothesis that this genetic marker is associated with increased vulnerability to the effects of psychostimulants.